Biomedical subjects

Charles A Dinarello

Publications and source records attributed to Charles A Dinarello.

At least 19 recordsLinked to original sources

PubMed2026

Reduced CCL/Be-specific CD4+ T cells in CCL3-deficient or peptide-MHCII CAR-T cell-treated mice.

In chronic beryllium disease (CBD), elevated levels of the inflammatory chemokines CCL3 and CCL4 in the lungs coincide with expanded populations of CD4+ T cells specific to beryllium-modified (Be-modified) peptides derived from these chemokines. Here, we generated HLA-DP2 transgenic (Tg) CCL3-deficient mice (CCL3-/-) that also lack CCL4 to investigate their role in disease development. Be-exposed CCL3-/- mice maintained normal numbers of lung macrophages and dendritic cells (DCs) but exhibited significantly reduced total and HLA-DP2-CCL/Be tetramer-specific CD4+ T cells, IFN-γ-producing CD4+ T cells, and peribronchovascular aggregates, consistent with attenuated inflammation. CCL3 was predominantly expressed in macrophages and DCs, and bone marrow chimera studies confirm that hematopoietic-derived DCs are the key regulators of CCL/Be-specific CD4+ T cell responses. RNA-seq of lung-resident CCL4/Be tetramer+ CD4+ T cells revealed a transcriptional profile enriched for inflammatory and cholesterol-metabolism pathways, with elevated expression of Ifng, Tnf, and Il17a. Moreover, Be-exposed HLA-DP2 Tg mice lacking TNF-α or treated with peptide-MHCII CAR-T cells targeting CCL4/Be-specific CD4+ T cells showed reduced T cell responses and cellular aggregates. These findings demonstrate that CCL3 and CCL4 promote CCL/Be-specific CD4+ T cell responses and highlight peptide-MHCII CAR-T cells as a potentially novel strategy for depleting self-peptide/Be-specific CD4+ T cells in CBD.

Animals↗

PubMed2006

Differential role and tissue specificity of interleukin-1alpha gene expression in atherogenesis and lipid metabolism.

OBJECTIVE: We examined the role of IL-1alpha and IL-1beta expressed by bone marrow-derived cells in atherogenesis and lipid metabolism. METHODS AND RESULTS: We first studied the effect of atherogenic diet on wild-type C57BL/6 IL-1alpha or IL-1beta deficient mice. IL-1alpha KO resulted in a comparatively higher total cholesterol levels, compared to WT and IL-1beta KO mice (398+/-10; 266+/-19; 223+/-13 mg/dl, respectively, p<0.001), due to higher non-HDL cholesterol. Nevertheless, aortic sinus lesion area was 56% lower in IL-1alpha KO (p<0.05) and 50% lower in IL-1beta KO (p=0.08), compared to WT mice. Likewise, SAA levels in IL-1alpha KO mice were markedly lower compared to WT and IL-1beta KO mice (31+/-14; 220+/-33 and 106+/-39 microg/ml, respectively, p<0.001). To study the specific role of bone marrow-derived IL-1, irradiated C57BL/6 mice were transplanted with either IL-1+/+, IL-1alpha-/- or IL-1beta-/- bone marrow cells. Despite similar lipoprotein levels, aortic sinus lesion area was 59% lower in IL-1alpha-/- transplanted (p<0.05) compared to IL-1+/+ transplanted mice. Lesion area in IL-1beta-/- was 33% lower than in IL-1+/+ recipient mice, but it was not statistically significant. CONCLUSION: We demonstrated that early lesion formation is accelerated specifically by bone marrow-derived IL-1alpha. Furthermore, we showed that the expression of IL-1alpha in cells other than the bone marrow plays a significant role in non-HDL cholesterol metabolism.

Amyloid↗

PubMed2006

Responses of IL-18- and IL-18 receptor-deficient pancreatic islets with convergence of positive and negative signals for the IL-18 receptor.

Pancreatic islets contain cells that produce IL-18 and cells that express IL-18 receptors. In experimentally induced diabetes, islet failure correlates with IL-18 levels and diabetes is delayed with blockade of endogenous IL-18. We studied islet-derived IL-18 and responses to IL-18 in a mouse model of islet allograft transplantation. In vitro, IL-18-stimulated islets produced nitric oxide, which closely matched islet apoptosis. By neutralizing IL-18 activity with IL-18 binding protein (IL-18BP), we observed that islets produce bioactive IL-18. In vivo, transgenic mice overproducing IL-18BP (IL-18BP-Tg) exhibited delayed hyperglycemia induced by beta cell toxic streptozotocin. Similarly, cultured IL-18BP-Tg islets were protected from streptozotocin-induced apoptosis. In the transplant model, islets grafted from WT to IL-18BP-Tg mice achieved prolonged normoglycemia (P = 0.031). Improved graft function was also observed by using IL-18-deficient islets transplanted into WT recipients, demonstrating that endogenous, islet-derived IL-18 mediates IL-18-driven graft damage. Unexpectedly, islets from mice deficient in IL-18 receptor alpha chain (IL-18R) exhibited rapid graft failure (P = 0.024; IL-18- versus IL-18R-deficient grafts in WT recipients). In related studies, IL-18R-deficient splenocytes and macrophages produced 2- to 3-fold greater amounts of IL-18, TNFalpha, macrophage inflammatory protein 1, macrophage inflammatory protein 2, and IFNgamma upon stimulation with Con A, Toll-like receptor 2 agonist, or anti-CD3 antibodies. These data reveal a role for islet-derived IL-18 activity during inflammation-mediated islet injury. Importantly, discrepancies between IL-18- and IL-18R-deficient cells suggest that IL-18Ralpha chain is used by an inflammation-suppressing signal.

Animals↗

PubMed2006

Triggering receptor expressed on myeloid cells-1 (TREM-1) amplifies the signals induced by the NACHT-LRR (NLR) pattern recognition receptors.

Triggering receptor expressed on myeloid cells-1 (TREM-1) is a member of a new family of myeloid receptors, encoded by a gene cluster linked to the MHC. Engagement of TREM-1 stimulates intracellular signals, resulting in activation of phagocytosis, neutrophil degranulation, and amplification of cytokine production induced by TLRs. In the present study, a novel property following engagement of TREM-1 is described, namely the amplification of cytokine production induced by the second major class of pattern recognition receptors, the NAIP, CIITA, HET-E, TP-1-leucine-rich repeat (NACHT-LRR; NLR) receptors, which recognize intracellular microorganisms through sensing their muropeptide components of peptidoglycan. The TREM-1/NLR synergism was observed for the production of TNF-alpha, IL-1beta, and IL-6, leading to an increase in cytokine production up to tenfold greater than the additive value of TREM-1 or muropeptide stimulation alone. Several putative mechanisms are proposed to be involved in the synergism between NLRs and TREM-1, including the increase in TREM-1 expression by NLR ligands, and of the expression of nucleotide oligomerization domain-2 receptor by TREM-1 engagement. In contrast, although caspase-1 modulates IL-1beta and IL-6 production after stimulation with anti-TREM-1 antibodies or NLR ligands, it does not appear to be responsible for the synergism between these two pathways. These findings demonstrate that TREM-1 acts on both major recognition pathways of bacterial structures: the extracellular TLR receptors, and the intracellular NLR molecules. This latter finding supports the concept that TREM-1 provides optimal amplification of cytokine-induced inflammation during the initiation of host defense.

Caspase 1↗

PubMed2006

Peripheral blood neutrophil activation patterns are associated with pulmonary inflammatory responses to lipopolysaccharide in humans.

Increased nuclear accumulation of NF-kappaB in LPS-stimulated peripheral blood neutrophils has been shown to be associated with more severe clinical course in patients with infection associated acute lung injury. Such observations suggest that differences in neutrophil response may contribute to the pulmonary inflammation induced by bacterial infection. To examine this question, we sequentially measured LPS-induced DNA binding of NF-kappaB in neutrophils collected from healthy humans on at least three occasions, each separated by at least 2 wk, and then determined pulmonary inflammatory responses after instillation of LPS into the lungs. Consistent patterns of peripheral blood neutrophil responses, as determined by LPS-induced NF-kappaB DNA binding, were present in volunteers, with a >80-fold difference between individuals in the mean area under the curve for NF-kappaB activation. The number of neutrophils recovered from bronchoalveolar lavage after exposure to pulmonary LPS was significantly correlated with NF-kappaB activation in peripheral blood neutrophils obtained over the pre-LPS exposure period (r = 0.65, p = 0.009). DNA binding of NF-kappaB in pulmonary neutrophils also was associated with the mean NF-kappaB area under the curve for LPS-stimulated peripheral blood neutrophils (r = 0.63, p = 0.01). Bronchoalveolar lavage levels of IL-6 and TNFRII were significantly correlated with peripheral blood neutrophil activation patterns (r = 0.75, p = 0.001 for IL-6; and r = 0.48, p = 0.049 for TNFRII. These results demonstrate that stable patterns in the response of peripheral blood neutrophils to LPS exist in the human population and correlate with inflammatory response following direct exposure to LPS in the lung.

Active Transport, Cell Nucleus↗

PubMed2006

Deficiency of interleukin-18 in mice leads to hyperphagia, obesity and insulin resistance.

Here we report the presence of hyperphagia, obesity and insulin resistance in knockout mice deficient in IL-18 or IL-18 receptor, and in mice transgenic for expression of IL-18 binding protein. Obesity of Il18-/- mice resulted from accumulation of fat tissue based on increased food intake. Il18-/- mice also had hyperinsulinemia, consistent with insulin resistance and hyperglycemia. Insulin resistance was secondary to obesity induced by increased food intake and occurred at the liver level as well as at the muscle and fat-tissue level. The molecular mechanisms responsible for the hepatic insulin resistance in the Il18-/- mice involved an enhanced expression of genes associated with gluconeogenesis in the liver of Il18-/- mice, resulting from defective phosphorylation of STAT3. Recombinant IL-18 (rIL-18) administered intracerebrally inhibited food intake. In addition, rIL-18 reversed hyperglycemia in Il18-/- mice through activation of STAT3 phosphorylation. These findings indicate a new role of IL-18 in the homeostasis of energy intake and insulin sensitivity.

Animals↗

PubMed2006

Immune phenomena involved in the in vivo regression of fibrosarcoma cells expressing cell-associated IL-1alpha.

Constitutive expression of cell-associated, but not secreted, interleukin-1alpha (IL-1alpha) by oncogene-transformed fibrosarcoma cells induced regressing tumors in mice, a phenomenon that was abrogated by the IL-1 inhibitor, the IL-1 receptor antagonist (IL-1Ra). On the contrary, non-IL-1alpha-expressing tumor cells induce progressive tumors in mice. In vivo and ex vivo experiments have shown that regression of IL-1alpha-positive fibrosarcoma cells depends on CD8(+) T cells, which can also be activated in CD4(+) T cell-depleted mice, with some contribution of natural killer cells. In spleens of mice bearing the non-IL-1alpha-expressing fibrosarcoma cells, some early and transient manifestations of antitumor-specific immunity, such as activation of specific proliferating T cells, are evident; however, no development of cytolytic T lymphocytes or other antitumor protective cells could be detected. In spleens of mice bearing the non-IL-1alpha-expressing fibrosarcoma cells, the development of early tumor-mediated suppression was observed, and in spleens of mice injected with IL-1alpha-positive fibrosarcoma cells, protective immunity developed in parallel to tumor regression. Treatment of mice bearing violent fibrosarcoma tumors with syngeneic-inactivated, IL-1alpha-positive fibrosarcoma cells, at a critical interval after injection of the malignant cells (Days 5-12), induced tumor regression, possibly by potentiating and amplifying transient antitumor cell immune responses or by ablation of tumor-mediated suppression. Membrane-associated IL-1alpha may thus serve as an adhesion molecule, which allows efficient cell-to-cell interactions between the malignant and immune effector cells that bear IL-1Rs and function as a focused cytokine with adjuvant activities at nontoxic, low levels of expression. Our results also point to the potential of using antitumor immunotherapeutic approaches using cell-associated IL-1alpha.

Animals↗

PubMed2006

Histone deacetylase inhibitors prevent exocytosis of interleukin-1beta-containing secretory lysosomes: role of microtubules.

A number of agents reducing interleukin-1beta (IL-1beta) activity are being developed as novel immunomodulatory and anti-inflammatory therapies. However, the elucidation of their molecular mechanism of action is required in the context of medical management of inflammatory diseases. Inhibitors of histone deacetylases (HDACs) are promising anticancer agents with pleiotropic activities. Of these, suberoylanilide hydroxamic acid has been reported to inhibit the production of several proinflammatory cytokines. In the present study, we investigated the effects of 2 HDAC inhibitors on IL-1beta secretion: suberoylanilide hydroxamic acid and a newly developed hydroxamic acid-derived compound ITF2357. These HDAC inhibitors do not affect the synthesis or intracellular localization of IL-1beta but both strongly reduce the levels of extracellular IL-1beta by preventing the exocytosis of IL-1beta-containing secretory lysosomes. At nanomolar concentrations, ITF2357 reduces the secretion of IL-1beta following ATP activation of the P2X7 receptor. Whereas the inhibition of HDACs results in hyperacetylation of tubulin, acetylation of HSP90 was unaffected. The reduction in IL-1beta secretion appears to be due to disruption of microtubules impairing lysosome exocytosis. Together, these observations indicate that a functional microtubule network is required for IL-1beta secretion and suggest that disruption of tubulin is the mechanism by which inhibitors of HDACs reduce the secretion of IL-1beta.

Calcium Signaling↗

PubMed2006

Histone hyperacetylation is associated with amelioration of experimental colitis in mice.

Inhibitors of histone deacetylases (HDAC) are being studied for their antiproliferative effects in preclinical cancer trials. Recent studies suggest an anti-inflammatory role for this class of compounds. Because inflammatory bowel disease is associated with an increased risk of malignancies, agents with antiproliferative and anti-inflammatory properties would be of therapeutic interest. HDAC inhibitors from various classes were selected and evaluated for their in vitro capacity to suppress cytokine production and to induce apoptosis and histone acetylation. Valproic acid (VPA) and suberyolanilide hydroxamic acid (SAHA) were chosen for further studies in dextran sulfate sodium- and trinitrobenzene sulfonic acid-induced colitis in mice. In vitro, inhibition of HDAC resulted in a dose-dependent suppression of cytokine synthesis and apoptosis induction requiring higher concentrations of HDAC inhibitors for apoptosis induction compared with cytokine inhibition. Oral administration of either VPA or SAHA reduced disease severity in dextran sulfate sodium-induced colitis. The macroscopic and histologic reduction of disease severity was associated with a marked suppression of colonic proinflammatory cytokines. In parallel to the beneficial effect observed, a dose-dependent increase in histone 3 acetylation at the site of inflammation was shown under VPA treatment. Furthermore, SAHA as well as VPA treatment resulted in amelioration of trinitrobenzene sulfonic acid-induced colitis, which was associated with an increase of apoptosis of lamina propria lymphocytes. Inhibitors of HDAC reveal strong protective effects in different models of experimental colitis by inducing apoptosis and suppressing proinflammatory cytokines, thereby representing a promising class of compounds for clinical studies in human inflammatory bowel disease.

Acetylation↗

PubMed2006

IL-32, a proinflammatory cytokine in rheumatoid arthritis.

IL-32 is a recently discovered cytokine that induces TNFalpha, IL-1beta, IL-6, and chemokines. We investigated whether IL-32 is expressed in the synovia of patients with rheumatoid arthritis (RA) and studied associations with disease severity and the presence of other cytokines. Immunohistochemistry revealed that IL-32 is highly expressed in RA synovial tissue biopsies, whereas IL-32 was not observed in synovial tissues from patients with osteoarthritis. Moreover, in synovial biopsies from 29 RA patients with active disease, the level of IL-32 staining correlated with erythrocyte sedimentation rate, a marker of systemic inflammation (R = 0.63 and P < 0.0003). Synovial staining of IL-32 also correlated with indices of synovial inflammation (R = 0.80 and P < 0.0001) as well as synovial presence of TNFalpha (R = 0.68 and P < 0.004), IL-1beta (R = 0.79 and P < 0.0001), and IL-18 (R = 0.82 and P < 0.001). IL-32 was a potent inducer of prostaglandin E(2) release in mouse macrophages and human blood monocytes, an important property for inflammation. After the injection of human IL-32gamma into the knee joints of naïve mice, joint swelling, with pronounced influx of inflammatory cells and cartilage damage, was observed. In TNFalpha-deficient mice, IL-32-driven joint swelling was absent and cell influx was markedly reduced, but loss of proteoglycan was unaffected, suggesting that IL-32 activity is, in part, TNFalpha-dependent. IL-32, strongly associated with TNFalpha, IL-1beta, and IL-18, appears to play a role in human RA and may be a novel target in autoimmune diseases.

Animals↗

PubMed2006

Proteinase 3 is an IL-32 binding protein.

IL-32, a recently discovered proinflammatory cytokine with four isoforms, induces IL-1beta, TNF-alpha, IL-6, and chemokines. Here, we used ligand (IL-32alpha) affinity chromatography in an attempt to isolate an IL-32alpha soluble receptor or binding protein. Recombinant IL-32alpha was covalently immobilized on agarose, and preparations of concentrated crude human urinary proteins were applied for chromatographic separation. A specific 30-kDa protein eluted from the column during acid washing and was identified by mass spectrometry as proteinase 3 (PR3) and confirmed by N-terminal microsequencing. PR3, a neutrophil granule serine protease, exists in a soluble or membrane form and is the major autoantigen for autoantibodies in the systemic vasculitic disease, Wegener's granulomatosis. The affinity of IL-32alpha to PR3 was determined by surface plasmon resonance. The dissociation constants were 2.65 +/- 0.4 nM for urinary PR3 and 1.2 +/- 0.05 nM for neutrophil-derived PR3. However, irreversible inactivation of PR3 enzymatic activity did not significantly change binding to the cytokine. Nevertheless, limited cleavage of IL-32 yielded products consistent with PR3 enzyme activity. Moreover, after limited cleavage by PR3, IL-32alpha was more active than intact IL-32alpha in inducing macrophage inflammatory protein-2 in mouse macrophages and IL-8 in human peripheral blood mononuclear cells. We suggest that PR3 is a specific IL-32alpha binding protein, independent of its enzymatic activity. However, limited cleavage of IL-32alpha by PR3 enhances activities of the cytokine. Therefore, specific inhibition of PR3 activity to process IL-32 or neutralization of IL-32 by inactive PR3 or its fragments may reduce the consequences of IL-32 in immune regulated diseases.

Animals↗

PubMed2006

Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in transgenic mice expressing transmembrane tumor necrosis factor alpha.

OBJECTIVE: The roles of the transmembrane and secreted forms of tumor necrosis factor alpha (TNFalpha) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFalpha have shown varying efficacy in RA patients, suggesting that anti-TNFalpha agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFalpha) and secreted TNFalpha. In this study, TNFalpha-knockout (TNFalpha-KO) mice that were genetically altered to express elevated levels of tmTNFalpha were constructed to further understand the roles of the 17-kd secreted, trimeric, and 26-kd transmembrane forms of TNFalpha. METHODS: A speed-congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26-kd tmTNFalpha and also secreting 17-kd trimeric TNFalpha (tmTNFalpha-transgenic), 2) TNFalpha-/- mice (TNFalpha-KO), and 3) transgenic mice overexpressing tmTNFalpha backcrossed to TNFalpha-KO mice (tmTNFalpha-transgenic/TNFalpha-KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis. RESULTS: The tmTNFalpha-transgenic/TNFalpha-KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2-4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNFalpha-transgenic mice also developed spontaneous-onset arthritis, but at a slower rate (100% incidence by 10-12 weeks). Clinical and histologic progression of arthritis in the tmTNFalpha-transgenic/TNFalpha-KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively). CONCLUSION: These data show that arthritis is sufficiently initiated and maintained in tmTNFalpha-transgenic/TNFalpha-KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNFalpha.

Animals↗

PubMed2006

The paradox of pro-inflammatory cytokines in cancer.

Cytokines such as IL-1 and TNF are primarily pro-inflammatory. The inflammation induced by these cytokines is reflected in the type of genes they induce. In the pathogenesis of carcinogenesis as well as tumor growth and spread, cytokines such as IL-1 and TNF induce chemokines that attract neutrophils. Neutrophils are key players in the production of reactive oxygen species and carcinogenesis. Another aspect of pro-inflammatory cytokines is the induction of adhesion molecules and metalloproteinases, both of which provide mechanisms for tumor invasion. Blocking cytokines, however, will reduce tumor growth and spread if administered at sufficient concentrations and will require parenteral therapy. However, blocking cytokines will not kill tumor cells nor prevent carcinogenesis. Blocking cytokines is best as an adjunct therapy together with tumorocidal drugs.

Cytokines↗

PubMed2006

Clinical and experimental approaches to the pathophysiology of interleukin-18 in cancer progression.

Interleukin-18 (IL-18, interferon [IFN]-gamma-inducing factor) is a proinflammatory cytokine converted to a biologically active molecule by interleukin (IL)-1beta converting enzyme (caspase-1). A wide range of normal and cancer cell types can produce and respond to IL-18 through a specific receptor (IL-18R) belonging to the toll-like receptor family. The activity of IL-18 is regulated by IL-18-binding protein (IL-18bp), a secreted protein possessing the ability to neutralize IL-18 and whose blood level is affected by renal function and is induced by IFNgamma. IL-18 plays a central role in inflammation and immune response, contributing to the pathogenesis and pathophysiology of infectious and inflammatory diseases. Because immune-stimulating effects of IL-18 have antineoplastic properties, IL-18 has been proposed as a novel adjuvant therapy against cancer. However, IL-18 increases in the blood of the majority of cancer patients and has been associated with disease progression and, in some cancer types, with metastatic recurrence risk and poor clinical outcome and survival. Under experimental conditions, cancer cells can also escape immune recognition, increase their adherence to the microvascular wall and even induce production of angiogenic and tumor growth-stimulating factors via IL-18-dependent mechanism. This is particularly visible in melanoma cells. Thus, the role of IL-18 in cancer progression and metastasis remains controversial. This review examines the clinical correlations and biological effects of IL-18 during cancer development and highlights recent experimental insights into prometastatic and proangiogenic effects of IL-18 and the use of IL-18bp against cancer progression.

Animals↗

PubMed2006

A pilot study of cytokine levels and white blood cell counts in the diagnosis of necrotizing fasciitis.

STUDY OBJECTIVES: To characterize the early cytokine response of patients presenting to the emergency department with necrotizing fasciitis (NF) and to determine whether serum cytokine levels and white blood cell (WBC) counts may be useful in distinguishing NF from other severe soft-tissue infections. METHODS: White blood cell counts and cytokine levels (IL-1beta, IL-1Ra, IL-6, IL-8, IL-18, and IFN-gamma) were measured in patients presenting to the emergency department with severe soft-tissue infections and high suspicion of NF. Necrotizing fasciitis was confirmed intraoperatively and by surgical pathology. Cytokines were measured via the liquid-phase electrochemiluminescence method. RESULTS: Thirty-five patients were enrolled, 18 were diagnosed with NF, and 17 were diagnosed with cellulitis and/or abscess (CAB). On admission, patients with NF had significantly higher WBC counts and lower levels of interleukin 1beta (IL-1beta) compared with patients with CAB. There were no statistically significant differences in the levels of the other cytokines between the 2 groups. CONCLUSION: Patients with NF have higher WBC counts and lower IL-1beta levels compared with patients with CAB.

Abscess↗

PubMed2006

T cell-mediated hepatic inflammation modulates adiponectin levels in mice: role of tumor necrosis factor alpha.

Experimental T cell-mediated hepatitis induced by concanavalin A (ConA) results in the initiation of an inflammatory response and the production of cytokines. Adiponectin is an adipocytokine produced by adipose tissue that is involved in the reciprocal regulation of other cytokines, including tumor necrosis factor alpha (TNF-alpha). Concanavalin A administration to C57BL/6J mice reduced circulating levels of adiponectin, whereas leptin was markedly increased. Adiponectin messenger RNA expression in adipose tissue was also decreased; however, the expression of both the adiponectin receptors remained unchanged. Neutralization of TNF-alpha reduced ConA-induced liver damage, and this was associated with restored circulating levels of adiponectin. These findings indicate that inflammation-induced TNF-alpha is a critical mediator of adipose-tissue-derived adiponectin in vivo.

Adiponectin↗

PubMed2006

Interleukin 1 and interleukin 18 as mediators of inflammation and the aging process.

In this review, 2 cytokines are discussed with respect to the inflammatory processes that are fundamental to aging and mortality. Both interleukin (IL)-1 and IL-18 are members of the same structural family (IL-1 family, or IL-F); there are presently 9 members of this family, but with the exception of IL-1alpha, IL-1beta, and IL-18, the others are antagonists or remain without known function. IL-1alpha is an intracellular cytokine with properties of both a cytokine and a transcription factor. IL-1beta and IL-18 are closely related; both possess a similar three-dimensional structure, and their respective precursor forms are inactive until cleaved by the intracellular cysteine protease caspase-1. Patients with mutations in the NALP3 gene, which controls the activity of caspase-1, readily secrete more IL-1beta and IL-18 and suffer from systemic inflammatory diseases. Patients with defects in this gene have high circulating concentrations of IL-6, serum amyloid A, and C-reactive protein, each of which decrease rapidly upon blockade of the IL-1 receptor, which suggests that IL-1beta contributes to the elevation of these markers of the inflammatory mechanisms of aging. Animal studies support the concept that IL-1beta and IL-18 participate in the pathogenesis of atherosclerosis. For example, overexpression of the IL-18 binding protein, a naturally occurring, specific inhibitor of IL-18, prevents the spontaneous development of atherosclerosis in apolipoprotein E-deficient mice. From human and animal studies, one may conclude that IL-1beta and IL-18 participate in fundamental inflammatory processes that increase during the aging process.

Aged↗

PubMed2006

Mycobacterium tuberculosis induces interleukin-32 production through a caspase- 1/IL-18/interferon-gamma-dependent mechanism.

BACKGROUND: Interleukin (IL)-32 is a newly described proinflammatory cytokine that seems likely to play a role in inflammation and host defense. Little is known about the regulation of IL-32 production by primary cells of the immune system. METHODS AND FINDINGS: In the present study, freshly obtained human peripheral blood mononuclear cells were stimulated with different Toll-like receptor (TLR) agonists, and gene expression and synthesis of IL-32 was determined. We demonstrate that the TLR4 agonist lipopolysaccharide induces moderate (4-fold) production of IL-32, whereas agonists of TLR2, TLR3, TLR5, or TLR9, each of which strongly induced tumor necrosis factor alpha and IL-6, did not stimulate IL-32 production. However, the greatest amount of IL-32 was induced by the mycobacteria Mycobacterium tuberculosis and M. bovis BCG (20-fold over unstimulated cells). IL-32-induced synthesis by either lipopolysaccharide or mycobacteria remains entirely cell-associated in monocytes; moreover, steady-state mRNA levels are present in unstimulated monocytes without translation into IL-32 protein, similar to other cytokines lacking a signal peptide. IL-32 production induced by M. tuberculosis is dependent on endogenous interferon-gamma (IFNgamma); endogenous IFNgamma is, in turn, dependent on M. tuberculosis-induced IL-18 via caspase-1. CONCLUSIONS: In conclusion, IL-32 is a cell-associated proinflammatory cytokine, which is specifically stimulated by mycobacteria through a caspase-1- and IL-18-dependent production of IFNgamma.

Caspase 1↗